Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

Zhang, Zhong Yin; Dodd, Garron T.; Tiganis, Tony

doi:10.1016/j.tips.2015.07.003

Cited by 158 publications

(137 citation statements)

References 120 publications

(170 reference statements)

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“…Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase that is widely expressed in the body, and negatively regulates leptin signaling by dephosphorylating Janus Activating Kinase 2 (JAK2) in the hypothalamus (Tsou and Bence, 2012, Myers et al, 2001, Zhang et al, 2015). Animals under HFD conditions show increased PTP1B expression in the hypothalamus (Zabolotny et al, 2008), and that increase facilitates the storage of body fat (Picardi et al, 2008, White et al, 2009, Zabolotny et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

et al. 2017

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Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.

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Section: Introductionmentioning

confidence: 99%

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

et al. 2017

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“…Recent studies also showed that TC-PTP has a critical role in the regulation of diabetes and obesity through its ability to modulate insulin and leptin signaling8. Neuronal cell-specific TC-PTP-deficient mice showed reduced high-fat diet-induced weight gain and enhanced leptin sensitivity with increased STAT3 phosphorylation in the hypothalamus after leptin administration, indicating that TC-PTP is involved in the development of leptin resistance9.…”

mentioning

confidence: 99%

Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

Lee

Kim

Baek

et al. 2017

Sci Rep

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Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling.

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“…(B2) Increased inflammation and reactive gliosis in the ARC impair the access of insulin and the responsivity of the AgRP and POMC neurones to insulin . (B3) The enhanced expression of negative regulators of IR signalling, such as TCPTP, PTP1B and SOCS3 within the hypothalamus attenuate insulin signalling . The decreased insulin signalling diminishes the ability of insulin to repress food intake, increase whole‐body energy expenditure, repress hepatic glucose production, promote glucose storage and influence lipid flux to maintain metabolic homeostasis.…”

Section: Insulin Transportmentioning

confidence: 99%

“…The tyrosine‐phosphorylated IRS proteins function as signalling nodes, recruiting adaptor proteins to transduce IR signalling and activate multiple downstream pathways, including the phosphatidylinositol 3 kinase (PI3K)/AKT and the mitogen‐activated protein kinase pathways to coordinate neuromodulatory gene transcription and neuronal excitability (Figure ) that influence energy and glucose homeostasis …”

Section: Insulin Signalling In the Cnsmentioning

confidence: 99%

Insulin action in the brain: Roles in energy and glucose homeostasis

Dodd

Tiganis

2017

J Neuroendocrinology

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A growing body of evidence from research in rodents and humans has identified insulin as an important neuoregulatory peptide in the brain, where it coordinates diverse aspects of energy balance and peripheral glucose homeostasis. This review discusses where and how insulin interacts within the brain and evaluates the physiological and pathophysiological consequences of central insulin signalling in metabolism, obesity and type 2 diabetes. K E Y W O R D SAgRP, energy homeostasis, glucose homeostasis, hypothalamus, insulin, POMC | INTRODUCTIONInsulin targets peripheral tissues, including skeletal muscle, adipose tissue, where it promotes glucose uptake from the blood, and the liver, where it inhibits gluconeogenesis and glycogenolysis and promotes glycogen synthesis to coordinately repress hepatic glucose production.In this way, insulin prevents postprandial hyperglycaemia and maintains euglycaemia. In addition to these peripheral targets, insulin also signals in the brain, although the physiological significance of this interaction has only recently started to emerge. Research over the past two decades has provided compelling evidence that central insulin signalling plays pivotal roles in many aspects of energy and glucose homeostasis (Figure 1). Given the epidemics of obesity and type 2 diabetes (T2D) in developed and increasingly developing countries, there is a pressing need to fully understand the mechanisms by which the body coordinates energy and glucose homeostasis. A key hallmark of obesity and T2D is insulin resistance, where defective insulin signalling downstream of the insulin receptor (IR) renders the peripheral target tissues of insulin insensitive to the action of insulin. What is becoming increasingly apparent is that neurones in the brain also become resistant to insulin; however the relative contributions of central insulin resistance to the development of obesity and T2D remain poorly understood.This review discusses the role of insulin in the brain with respect to coordinating glucose metabolism with energy expenditure. In particular, we discuss our understanding of the locations and mechanisms by which insulin elicits its effects in the brain, its influence on glucose metabolism and energy expenditure, and the potential contributions of central insulin resistancein the development of obesity and the metabolic syndrome.

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Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

Cited by 158 publications

References 120 publications

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

Insulin action in the brain: Roles in energy and glucose homeostasis

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